ll new diagnoses of colorectal and endometrial cancer should have tumour MSI / IHC as outlined in the
cancer test directory and the Lynch syndrome handbook for Alliances in order to identify dMMR tumours and
additional testing that suggests Lynch Syndrome. This may include BRAF testing in MLH1 deficient
colorectal cancers and somatic MLH1 hypermethylation testing in BRAF negative colorectal cancers and all
MLH1 deficient uterine cancers. Somatic MLH1 hypermethylation testing is included on the Cancer Test
Directory under M1.5.
1. Clinical Criteria for germline testing in an affected individual
The proband has a dMMR tumour where results of additional testing suggest Lynch syndrome. This
may include BRAF testing in MLH1 deficient colorectal cancers and somatic MLH1 hypermethylation
testing in BRAF negative colorectal cancers and all MLH1 deficient uterine cancers
a. The affected proband comes from a modified Amsterdam criteria positive family irrespective of the
dMMR status of the tumour
b. Personal or family history suggestive of Constitutional Mismatch Repair Deficiency (CMMRD) with
Wimmer score =>3
c. Deceased affected individual meets criteria and a previously stored constitutional blood/DNA sample
is available.
2. Clinical criteria for MSI /IHC testing on a stored tumour sample prior to germline testing
a. Personal/family history of colorectal cancers reaching Modified Amsterdam Criteria (≥ 3 cases of
Lynch related cancer over ≥2 generations with ≥1 case diagnosed <50 years) OR b. c. d. Any lynch-related cancer* <50 years (excluding isolated pancreas, prostate or gastric cancers) Two Lynch-related cancers (any age, one is colorectal or endometrial), OR Lynch-related cancer and ≥ 1 first degree relative has Lynch-related cancer (both occurred ≤60 years, one is colorectal or endometrial), OR e. Lynch-related cancer and ≥ 2 relatives (first / second / third degree relatives) have Lynch-related cancer (all occurring ≤75years, one is colorectal or endometrial), OR f. Lynch-related cancer and ≥ 3 relatives (first / second / third degree relatives) have Lynch-related cancer (occurring any age, one is colorectal or endometrial) *Lynch-related cancers comprise: Colorectal cancer, Endometrial cancer, Epithelial ovarian cancer, Urothelial cancers, Transitional cell cancer of renal pelvis, cholangiocarcinoma, Small bowel and upper gastrointestinal cancers, Glioblastoma, endocervical cancer, multiple sebaceous tumours, prostate, gastric and pancreas 3. Clinical Criteria for somatic (tumour) Lynch syndrome panel testing a. Proband has colorectal or endometrial cancer with a dMMR tumour with normal BRAF and somatic MLH1 hypermethylation analysis AND germline testing did not reveal a pathogenic variant OR personal/family pattern of disease whereby demonstration of acquired MMR variants (and therefore exclusion of constitutional MMR abnormality) enables downscaling of surveillance b. Deceased affected individual with colorectal or endometrial cancer ≤60 years AND tumour featuring high/intermediate MSI or loss of staining of MMR protein(s) on IHC, AND one first degree relative with Lynch-related cancer ≤60 AND no living affected individual is available for genetic testing. 4. Clinical Criteria for germline testing in an unaffected individual a. b. First degree relative affected with Lynch-related cancer, AND Family history of colorectal cancer/Lynch-related cancers reaches Amsterdam Criteria (≥3 cases over ≥2 generations with ≥1 case affected <50 years) AND c. Tumour sample analysis from affected family member has been attempted and is not possible, failed, indeterminate or indicates MMR deficiency (via IHC or MSI), AND d. e. Somatic sequencing is not possible, or failed, AND No living affected individual is available for genetic testing 5. Criteria for germline MLH1 promoter methylation a. Families where MLH1 promotor methylation has been identified in tumour tissue in >1 affected
individual with colorectal cancer ≤ 60
NOTE: The proband’s cancer and majority of reported cancers in the family should have been confirmed
190 v7.1 January 2025
Testing of unaffected individuals can only be carried out by Clinical Genetics Services
Genetic testing may occasionally be appropriate outside these criteria following discussion at a specialist
MDT with a cancer geneticist present
Referrals for testing will be triaged by the Genomic Laboratory; testing should be targeted at those where a
genetic or genomic diagnosis will guide management for the proband or family.

All new diagnoses of colorectal and endometrial cancer should have tumour MSI / IHC as outlined in the cancer test directory and the Lynch syndrome handbook for Alliances in order to identify dMMR tumours and
additional testing that suggests Lynch Syndrome. This may include BRAF testing in MLH1 deficient
colorectal cancers and somatic MLH1 hypermethylation testing in BRAF negative colorectal cancers and all
MLH1 deficient uterine cancers. Somatic MLH1 hypermethylation testing is included on the Cancer Test
Directory under M1.5.
1. Clinical Criteria for germline testing in an affected individual
The proband has a dMMR tumour where results of additional testing suggest Lynch syndrome. This
may include BRAF testing in MLH1 deficient colorectal cancers and somatic MLH1 hypermethylation
testing in BRAF negative colorectal cancers and all MLH1 deficient uterine cancers
a. The affected proband comes from a modified Amsterdam criteria positive family irrespective of the
dMMR status of the tumour
b. Personal or family history suggestive of Constitutional Mismatch Repair Deficiency (CMMRD) with
Wimmer score =>3
c. Deceased affected individual meets criteria and a previously stored constitutional blood/DNA sample
is available.
2. Clinical criteria for MSI /IHC testing on a stored tumour sample prior to germline testing
a. Personal/family history of colorectal cancers reaching Modified Amsterdam Criteria (≥ 3 cases of
Lynch related cancer over ≥2 generations with ≥1 case diagnosed <50 years) OR b. c. d. Any lynch-related cancer* <50 years (excluding isolated pancreas, prostate or gastric cancers) Two Lynch-related cancers (any age, one is colorectal or endometrial), OR Lynch-related cancer and ≥ 1 first degree relative has Lynch-related cancer (both occurred ≤60 years, one is colorectal or endometrial), OR e. Lynch-related cancer and ≥ 2 relatives (first / second / third degree relatives) have Lynch-related cancer (all occurring ≤75years, one is colorectal or endometrial), OR f. Lynch-related cancer and ≥ 3 relatives (first / second / third degree relatives) have Lynch-related cancer (occurring any age, one is colorectal or endometrial) *Lynch-related cancers comprise: Colorectal cancer, Endometrial cancer, Epithelial ovarian cancer, Urothelial cancers, Transitional cell cancer of renal pelvis, cholangiocarcinoma, Small bowel and upper gastrointestinal cancers, Glioblastoma, endocervical cancer, multiple sebaceous tumours, prostate, gastric and pancreas 3. Clinical Criteria for somatic (tumour) Lynch syndrome panel testing a. Proband has colorectal or endometrial cancer with a dMMR tumour with normal BRAF and somatic MLH1 hypermethylation analysis AND germline testing did not reveal a pathogenic variant OR personal/family pattern of disease whereby demonstration of acquired MMR variants (and therefore exclusion of constitutional MMR abnormality) enables downscaling of surveillance b. Deceased affected individual with colorectal or endometrial cancer ≤60 years AND tumour featuring high/intermediate MSI or loss of staining of MMR protein(s) on IHC, AND one first degree relative with Lynch-related cancer ≤60 AND no living affected individual is available for genetic testing. 4. Clinical Criteria for germline testing in an unaffected individual a. b. First degree relative affected with Lynch-related cancer, AND Family history of colorectal cancer/Lynch-related cancers reaches Amsterdam Criteria (≥3 cases over ≥2 generations with ≥1 case affected <50 years) AND c. Tumour sample analysis from affected family member has been attempted and is not possible, failed, indeterminate or indicates MMR deficiency (via IHC or MSI), AND d. e. Somatic sequencing is not possible, or failed, AND No living affected individual is available for genetic testing 5. Criteria for germline MLH1 promoter methylation a. Families where MLH1 promotor methylation has been identified in tumour tissue in >1 affected
individual with colorectal cancer ≤ 60
NOTE: The proband’s cancer and majority of reported cancers in the family should have been confirmed
190 v7.1 January 2025
Testing of unaffected individuals can only be carried out by Clinical Genetics Services
Genetic testing may occasionally be appropriate outside these criteria following discussion at a specialist
MDT with a cancer geneticist present
Referrals for testing will be triaged by the Genomic Laboratory; testing should be targeted at those where a
genetic or genomic diagnosis will guide management for the proband or family.